Testosterone is crucial for male health. The normal human male testes produces four to eight milligrams of testosterone daily. There is considerable variation in the reported half-life of testosterone, reported values range from 10 to 100 minutes. Circulating testosterone exhibits a diurnal variation in normal young men. See, Southren A K, et al., J Clin Endocrinol 27:686–694 (1967). Testosterone levels peak at about approximately 6:00 to 8:00 a.m. and decline during the remainder of the day. This testosterone has effects on a variety of tissues including, for instance, brain, liver, muscle, bone and bone marrow, blood vessels, skin, prostate and penis. Men with testosterone deficiency may have symptoms of depression, reduced libido, and low energy. They may suffer from anemia, osteoporosis and debilitating muscle weakness. Testosterone replacement therapy can improve well-being, maintain bone and muscle mass, and retain healthy sexual function.
Testosterone is also important in women's health. Androgens are secreted by both the ovaries and adrenal glands in women. Provision of testosterone in androgen-deficient women can improve their libido, energy, muscle mass and strength, and bone mineral density.
In the United States, testosterone replacement therapy primarily involves administration of testosterone by intramuscular injection, transdermal patch, or gels. The intramuscular injections must be given every 1–3 weeks to maintain normal serum testosterone levels and can be painful. Testosterone patches may cause moderate to severe skin reactions in more than half of subjects due to the vehicle that facilitates testosterone absorption across the skin. The testosterone gel is effective but expensive and care must be taken to avoid inadvertent exposure to women and children.
In the United States there are no FDA approved non-alkylated (and therefore safe) testosterone oral medications for administering testosterone. Thus, improved oral therapies for testosterone replacement are greatly needed. However, oral administration of unmodified testosterone at doses up to 100 mg have little effect on serum testosterone levels in levels deficient men (see, Foss G L, et al. Lancet 1:502–504(1939) and Nieschlag E, et al., Acta Endocrinol (Copenh) 79:366–374 (1975)). Several decades ago, 200 mg doses of oral testosterone were shown to elevate serum testosterone levels to the low normal range for up to eight hours (see, Johnsen S G et al., Lancet 2:1473–1475 (1974) and Daggett P R et al., Hormone Res. 9:121–12922,23(1978)). Such serum testosterone levels were thought to be insufficient for clinical use and research into using unmodified oral testosterone was largely abandoned. A second issue relating to oral testosterone therapy is elevations in the potent androgen dihydrotestosterone (DHT) derived from conversion of testosterone by the enzyme 5-α reductase. Alkylated steroids having greatly improved oral bioavailablity have been developed. However, alkylation has been associated with a greatly increased risk of hepatotoxicity. Therefore, these synthetic compounds are far from an ideal solution.
Testosterone undecanoate (TU) is a testosterone ester currently used clinically in Europe and Canada for the treatment of testosterone deficiency. Oral TU therapy results in therapeutic increases in serum testosterone; however, it also results in elevations in serum DHT well above the normal range. Administration of lower doses of 100–200 mg doses of unmodified testosterone or non-alkylated “esterified” testosterone to testosterone deficient men does not elevate serum testosterone levels into the therapeutic range. A principal difficulty with the administration of oral testosterone is its rapid absorption into the hepatic circulation and subsequent destruction in the liver. The large doses that would be required to maintain therapeutic levels of testosterone over the course of therapy make testosterone therapy by oral administration impractical (Daggert et al. Hormone Research 9:121–129 (1978) and non-oral routes of administration of testosterone are much preferred. It is thought that specifically with testosterone undecanoate that some small portion of a large oral dose may be actually absorbed via the lympatic system and thus avoid the ‘first pass’ effect of hepatic metabolism on the bioavailability of oral testosterone. Oral methods also may suffer from undesirable pharmacokinetic profile. They can result also in supra-physiologic testosterone concentrations followed by a too-rapid return to baseline.
A third issue relating to oral testosterone therapy is the role of food in the absorption of TU. The absorption of TU is dramatically improved by food intake due to the lipid-like structure of TU (see, Bagchus W M et al., Pharmacotherapy 23(3):319–25 (2003)). Knowledge of the affect of food on the absorption of orally dosed testosterone and testosterone esters will be very important in future studies of androgen therapy.
While overall only a very small fraction of endogenously produced testosterone is metabolised to DHT, a major factor in testosterone therapy is the conversion of testosterone to dihydrotestosterone (DHT). In some target organs, DHT is the more active androgen and the effects of testosterone are mediated by the conversion of testosterone to DHT by 5-α-reductase activity in the target organ. Both testosterone and DHT are metabolized to androstandiol, the 3α-diol of DHT that is rapidly metabolized by glucuronide conjugation and excreted in the urine. Observations of males with 5-α-reductase deficiency suggest that muscle, the penis, spermatogenesis, maintenance of libido, sexual behavior, and feedback inhibition of gonadotropin secretion primarily respond to testosterone whereas skin and the prostate primarily respond to DHT and that inhibitors of 5-α-reductase would be useful for the treatment or prevention of acne, baldness, female hirsutism, benign prostate hypertrophy, and prostatic cancer. Thus, the formation of DHT from testosterone and the effects of DHT on such target organs can be greatly reduced by adminstration of 5-α-reductase inhibitors.
Two isoenzymes of 5-α-reductase have been found: Type 1 and Type 2. The isoenzymes vary in their target tissue distribution (Rittmaster, J. of Andrology 18(6):582 (1997). 5α-reductase Type I is found largely in skin and the liver, while 5α-reductase Type II is located mainly in the male urogenital tract both during fetal and adult life. For instance, Type 1 predominates in the sebacious glands and Type 2 predominates in the prostate gland and hair follicles. Finasteride is predominantly an inhibitor for the Type 2 isoenzyme. Administration of finasteride has been reported to reduce serum DHT levels by 70% and prostate DHT levels by 90%. Combined inhibition of the Type 1 and Type 2 isoenzymes can reduce circulating DHT levels by 97%. While adminstration of finasteride can reduce serum DHT levels by 70%, the levels of testosterone itself are not appreciably changed. Typically testosterone levels only increase by about 10% in men given finasteride (Gormley et al. J. Clin. Endocrinol. Metab. 7:1136–41 (1990).
The combined use of exogenous androgen therapies with a 5-α-reductase inhibitor has been recently disclosed (see Amory et al., J. Clin. Endocrinol. and Metabol. 89(2):503–510 (2004); see also U.S. Pat. No. 6,696,484 to Liao et al; U.S. Patent Application Publication No. 20030203043; and U.S. Patent Application Publication No. 20040110733). Amory et al., in particular, have investigated the effects of intramuscularly administered testosterone and the intramuscularly administered testosterone with finasteride in men with low serum testosterone. Amory et al. reported that finasteride greatly decreased serum DHT levels in the men but that finasteride was without substantial effect on the levels of serum testosterone in the men who received the testosterone by intramuscular administration.
The present invention provides for a practical means of oral androgen therapy. The invention is based upon the surprising discovery that despite the relatively minor role of 5-α-reductase to the overall metabolism or serum level of testosterone, orally administered finasteride and dutasteride nevertheless greatly increase the availability of testosterone and testosterone esters when these androgens are administered by the oral route as opposed to other routes (e.g., intramuscular, transdermal). With this discovery, it becomes practical to provide oral testosterone replacement therapy by administering testosterone, testosterone esters, and testosterone precursors in a combination therapy with modulators of testosterone bioavailability by the oral route.